Heart Valve Replacements: Requirements and Evolution

Advanced Structural Aspects of Biomaterials Fall 2013

Sonia Travaglini 1 , Hao Ji 1 , Yangxin Chen 1 , Sofia Cafaggi 2 , Britta Berg-Johansen 2 C215 & 2 BioE C222 Advanced Structural Aspects of Biomaterials University of California, Berkeley
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Table of Contents

TABLE OF CONTENTS --------------------------------------------------------------------------------------------------------------- II 1. EXECUTIVE SUMMARY----------------------------------------------------------------------------------------------------------- 1 2. ANALYSIS OF STRUCTURAL FUNCTION & REQUIREMENTS OF THE DEVICE ------------------------------ 2 2.1 HEART VALVE DYNAMICS ------------------------------------------------------------------------------------------------------------- 2 2.2 HEART VALVE HEMODYNAMICS ------------------------------------------------------------------------------------------------------ 2 2.4 MATERIAL PROPERTY REQUIREMENTS ----------------------------------------------------------------------------------------------- 3 2.5 BI-LEAFLET HEART VALVES ----------------------------------------------------------------------------------------------------------- 3 3. DESIGN & MATERIAL EVOLUTION ------------------------------------------------------------------------------------------ 4 3.1 DEVICE DESIGN -------------------------------------------------------------------------------------------------------------------------- 4 3.2 DEVICE DESIGN EVOLUTION ----------------------------------------------------------------------------------------------------------- 5 3.3 DEVICE MATERIALS EVOLUTION------------------------------------------------------------------------------------------------------ 6 4. CASE STUDY: TRANSCATHETER AORTIC VALVE REPLACEMENT ---------------------------------------------- 7 4.1 TAVR STANDARDS --------------------------------------------------------------------------------------------------------------------- 8 4.2 TRADE NAMES & MARKETING -------------------------------------------------------------------------------------------------------- 9 5. GENERAL CARDIAC VALVE PROSTHESES STANDARD --------------------------------------------------------------- 9 6. FUTURE MATERIALS ------------------------------------------------------------------------------------------------------------- 10 7. CONCLUSIONS ---------------------------------------------------------------------------------------------------------------------- 10 8. REFERENCES ------------------------------------------------------------------------------------------------------------------------ 11

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1. Executive Summary Replacement heart valves provide a life-saving therapy to replace the vital functions of the arterial and mitral heart valves in pumping blood throughout the body. Acting as one-way flow regulators, the valves use soft flexible tissues that can be challenging to replicate with synthetic materials, particularly in the highly demanding in vivo environment of the heart. Prosthetic valves require a long service life (~18 years) with cyclic loading, and therefore must be highly resistant to fatigue. There are currently two main types of valves, Mechanical Heart Valve (MHV) and Tissue Heart Valve (THV). Modern mechanical valves are more durable, but require anticoagulant treatment. Tissue heart valves have a limited lifespan and the associated risk of immunological rejection. Decision on which valve to employ is done on a case-by-case basis by considering patient preference, associated health risks, age, and activity level. The MHV devices started with the ball-and-cage design; the first design utilized a silicon ball valve and metal outer structures, first using stainless steel and then the more biocompatible, popular medical material, titanium. Due to problems with corrosion and immunoresponse, these designs then gave way to non-tilting disk valves, followed by tilting disk valves, but all such designs suffered higher levels of turbulent blood flow, damage to blood platelets, and the formation of blood clots from surface adhesion of proteins, which can be a fatal complication. In the late 1970‟s the first replacement bivalves were introduced, which offered improved blood flow and thus reduction of the load on the heart. The departure from metallic structures the introduction of pyrolytic carbon, with greatly improved materials properties, enabled smoother materials and smaller and thinner geometries that were less likely to suffer adhesion, leading to the current generation of pyrolytic carbon bi-leaflet designs. The future trends of the materials used for heart valve devices indicate decreasing use of metallic materials, partly due to the complex problems associated to corrosion and partly due to the problem of time-dependent strain hardening and suggest the continued use of pyrolytic carbon and increasing use of polymeric materials. For high-risk patients who cannot undergo open heart surgery, Transcatheter Aortic Valve Replacements (TAVR) offer a novel, minimally invasive treatment. The Edwards SAPIEN TAVR was recently approved by the FDA and has already saved lives of hundreds of high-risk patients with aortic stenosis. It combines bovine pericardial tissue with a stainless steel stent for insertion and a polymer skirt to prevent leakage. While this transcatheter approach improves survival rates in highrisk patients, the insertion through the arteries leads to increased risk for strokes and vascular complications. Smaller-diameter catheters and surgeon experience may decrease complications in the future.

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2. Analysis of Structural Function & Requirements of the Device A human heart valve can be replaced with an implanted mechanical or tissue heart valve in the aortic or mitral position. THVs, or biological prostheses, are organic heart valves utilizing tissues from animals or human organ donors. A more in depth comparison between MHVs and THVs is provided in Section 3. In general, heart valves have very precise requirements due complex anatomy and fluid dynamics in the heart. 2.1 Heart Valve Dynamics The structural requirements of a heart valve primarily deal with forces from blood flow through the valve, and the dynamic mechanisms of the valve motion. The biological tissues surrounding valves have complex stress and strain interactions in biological materials, and the complexity of valve anatomy makes it difficult to theoretically determine the functional role and importance of individual components. An analysis of the behavior of a heart valve in the body, summarized below, gives insight into the geometric and material properties required to enable the functioning of the valve in vivo over its service life.  The amount of cycles required from the valve is extremely demanding (i.e. 18 years x 365 days x 24 hours x 60 minutes x 60 beats per minute = 570 million cycles).  Leaflets experience large, anisotropic strains during closure in response to small transvalvular pressure gradients.  Once the valve is closed, there is no further leaflet deformation. This means the leaflet is bending over time, which may cause fatigue. 2.2 Heart Valve Hemodynamics The mechanisms ensuring the proper function of heart valves are essentially controlled by the surrounding hemodynamic environment. Heart valves all essentially function to facilitate unidirectional blood flow. Generally, in a healthy heart, blood flows through the valve to a peak velocity of 1.35 ± 0.35 m/s. Adverse axial pressure differences cause the flow along the aortic wall to decelerate and reverse direction. This results in vortices in the sinuses behind the valve leaflets, and these vortices push the leaflets away from the sinus wall to a closed position. An important consideration is the stress on the heart as blood goes through the three different streams at different velocities. Increased demand levels may damage or even kill a patient with a weak heart. Research is ongoing to improve device design and hence decrease stress to the heart. 2.3 General Requirements Based on the function of a heart valve, requirements of prosthetic heart valves include:  Excellent hemodynamics: reduction of turbulent flow is required to avoid trauma to the blood cells and to reduce the load on the heart (Chandran et al., 2003)  Excellent implantability: to ensure the valve placement is secure, tissue ingrowth is required at the sewing cuff (Pruitt, 2011)  Minimal regurgitation (amount of blood lost upstream as the valve closes)  Minimal cavitation (the rapid formation of vaporous microbubbles in the fluid due to a local drop of pressure below the vaporization pressure at a given temperature)  Haemocompatibility  Durability: must undergo years of cyclic loading  High thrombo-resistance: must resist clotting of blood  Radiopacity for post-surgical monitoring  Resistance to strut fracture, pitting, and corrosion in MHVs
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Resistance to leaflet rupture and immunological rejection in THVs High manufacturability and low cost

2.4 Material Property Requirements Based on the general requirements, the required material properties for a bileaflet MHV are the following:  Stiffness of outer edge to resist deformations within the blood vessel tube from blood flow  Flexibility of leaflets to allow blood flow  Creep resistance to prevent deformation of the device over time  Wear resistance to resist mechanical wear from blood flow (including turbulent flow)  Strength to resist small deformation within the blood vessel tube from blood flow  Fatigue resistance, especially considering the significant number of cycles within a service life  Corrosion resistance to prevent debris release and structural failure over time  Non-immunoresponsive: prevention of collagen formation on MHV

Figure 1. On-X Prosthetic Heart Valve manufactured by On-X Life Technologies (Adapted from On-X Life Technologies, 2013)

2.5 Bi-leaflet Heart Valves The bi-leaflet MHV design is considered to have the best flow dynamics. The leaflets open completely, allowing very little resistance to the blood flow. This also corrects the problem of turbulence and blood cell damage associated with central flow [5]. The bi-leaflet MVH was first introduced in 1978, and the basic design consists of two semicircular leaflets which pivot on hinges inside a suture ring or cuff (Figure 1). The suture ring houses all the functional parts, and is the only part that is attached to the heart tissue. The two leaflets have the same function as natural cusps and are supported by hinges. As the blood flows through the valve, it encounters the two thin leaflets, which divide the passage into three sections. Consequently, the velocity of the blood through the valve will differ based on which part of the heart valve the blood comes through. A limitation of the bi-leaflet MHV is that it allows a small amount of backflow due to the gap between the two leaflets when closing, as well as the gaps on the circumference of the valve. Normally the degree of backflow is inconsequential. However, if backflow increases and becomes significant, the valve needs to be replaced.
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3. Design & Material Evolution 3.1 Device Design A prosthetic heart valve is designed to mimic the characteristics of a normal native heart valve: maintaining unimpeded forward flow through the heart and from the heart into the major blood vessels connected to the heart, the pulmonary artery, and the aorta. The pressure differential on each side of the valve determines whether it opens or closes. Due to a number of diseases, any of the four heart valves in mammals may malfunction and result in stenosis (impeded forward flow) and/or backward flow (regurgitation). These processes may lead to heart failure, so a prosthetic heart valve is intended to replace the diseased one. As mentioned in Section 2, the two main types of heart valves are mechanical and tissue (bioprosthetic) valves, as shown in Figure 2. Modern mechanical valves can last indefinitely, but require lifelong treatment with anticoagulants. Tissue heart valves do not require the use of anticoagulant drugs, but have a limited lifespan and have the associated risk of immunological rejection. Bi-leaflet valves feature two semilunar disks attached to a rigid valve ring by small hinges. The open valve consists of 3 orifices: small, slit-like central orifice between the two open leaflets and two larger semicircular orifices laterally. Mono-leaflet valves: single disk secured by lateral or central metal struts; the opening angle of the disk relative to valve annulus results in two distinct orifices of different sizes. Caged ball valves feature a silastic ball with a circular swing ring and a cage formed by three metal arches.

Figure 2: Valves; Mechanical Bileaflet, B. Mechanical Monoleaflet, C. Mechanical Caged Ball, D & E Tissue Porcine bioprosthetic, F. Tissue Stentless Bioprosthetic (Adapted from Pibarot, 2009)

Porcine bioprosthetic valves consist of three porcine aortic valve leaflets cross-linked with glutaraldehyde and mounted on a metallic or polymer supporting stent. Pericardial valves are fabricated from sheets of bovine pericardium mounted inside or outside a supporting stent. F. In an effort to improve valve hemodynamics and durability, several types of stentless bioprosthetic valves have been developed (Figure 2 – F). Stentless bioprostheses are manufactured from whole porcine aortic valves or fabricated from bovine pericardium in an attempt to improve valve hemodynamics. The decision of which type of valve to employ is highly variable among patients, as several considerations are taken into account. A schematic of a decision tree that portrays the decision-making process regarding which type of prosthetic valve to employ is shown on Figure 3 (Pibarot, 2009).

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Figure 3: Decision-making algorithm for valve selection on individual patients (Adapted from Pibarot, 2009)

3.2 Device Design Evolution Mechanical heart valves initially did not mimic biological designs created by nature, such as the more modern tri-leaflet tissue valves. Hufnagel, the very first design, featured a tubular design with a ball value but was designed as an assistive device, not a valve replacement. The Starr-Edwards caged ball valve provided entire valve replacement, but at the cost of needing anticoagulant therapy to prevent thrombosis as blood clots form due to protein adhesion to the synthetic surface. The ball valve design proved very successful and improved versions are still in production today, however the design also has drawbacks, including that the surface area of the ball reduced blood flow and increased the load on patient‟s heart, and damage to blood platelets continues to be an issue with mechanical valves.

Fig 4: Heart Valve Design Evolution (Adapted from Gott, 2003, and Butany, 2003)

Tilting disk replacement valves developed from non-tilting disks, resolving the former‟s design issue of the loose disk causing turbulent blood flow. The modern day replacement bivalves were introduced in the late 1970‟s, and more closely mimic the structure and flow patterns of natural heart valves, offering improved blood flow and reduction of the load on the heart.
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3.3 Device Materials Evolution The flow of blood through the valve is one of the most important design and materials selection factors. Non-laminar flow and turbulent backflow pose serious problems. More modern valves reduce the surface coefficient of friction which improves blood flow and reduces risk of protein surface adhesion leading to embolisms (Cannegieter, 1994), as does the physical design of the new bi-valve device designs, which also closer mimic the right back-pressure of blood flow required for nearnatural operation.

Fig 5: Heart Valve Materials Evolution (Adapted from Gott, 2003, and Butany, 2003)

Ball valves began by using stainless steel and progressed to titanium, offering sufficient strength and stiffness, biocompatibility, and most importantly improved corrosion resistance. If left unaddressed, corrosion contributes to structural failures through fretting. Silicone was used for the ball material, offering low surface friction coefficient and resistance to strainhardening over time. Materials which suffer age-hardening (timeinduced strain hardening), typically seen in Fig 6: Replacement Heart Valve Materials Evolution materials including metals and polymers, can result in brittle failure and so are therefore unsuitable without careful control of their yield strength and modulus properties for their entire service life. The discovery of pyrolytic carbon, sometimes also termed pyrolytic graphite moved designs and devices to a whole new level and improved patient life expectancy, due to its excellent low surface friction, resistance brittle failure and also being totally inert – a real advantage as biocompatibility is vital property for heart valve materials. Fixation is a very important factor for heart valve devices, as hard inflexible metals and polymers must be secured to flexible, elastic bio-cellular walls, and any travel or dislodgement can cause the device to be regurgitated, overgrown with tissue causing complications, or even cause sudden death (Vesely, 2003). The solution continues to be a woven fabric with non-absorbable sutures which can last the service life. Early PTFE fabric covered ball valves showed cloth wear (Kaufman, 1982) but

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continues to be the fabric of choice to anchor many devices, most recently being carbon coated in the Carbo-Medics devices. Fatigue continues to be the greatest challenge and highest risk of failure – such a critical device has fatal consequences, such as the failure of 1980‟s valve which resulted in patient deaths and a major program of recovery of the devices – a costly and difficult process. One aspect of the challenges fatigue brings to materials selection is to find materials which can withstand the long service life – unlike less critical devices, heart valves may have a service life of +18 years. When the number of cycles is considered, only materials which can provide long-term resistance to becoming brittle or losing structural integrity can be used, and even accurately testing these materials to validate this can be problematic. Sterilization also places design and materials limitations, as high temperature sterilization methods (eg autoclave) are unsuitable for polymers which may have a low melt temperature, radiation based sterilization (e.g. Gamma radiation) may induce cross-linking in polymers which leads to brittle failures, so gas-plasma sterilization is the current method of choice so far known of free of damaging effects.

4. Case Study: Transcatheter Aortic Valve Replacement Just a few months ago, a vivacious 100-year-old woman received a new type of artificial heart valve that saved her life. Maxine Tuttle was literally drowning from heart failure as fluid filled her lungs, when she was given a Transcatheter Aortic Valve Replacement (TAVR) that restored her circulation. She was chosen for the procedure because of her otherwise healthy condition and her love of life. Of the procedure, Maxine said, “Isn‟t it wonderful? One day I couldn‟t breathe, and then just a few days later, I could breathe. I‟m very happy” (The Sacramento Bee, 2013). TAVRs are novel valve replacements that are implanted through a catheter, for patients who are unable to undergo open-heart surgery for valve replacement because of advanced age and/or coexisting conditions . In clinical practice, 30% of patients with severe aortic stenosis fall under this category (Oregon Heart & Vascular Institute, 2013). Though only in its beginnings, this minimally invasive alternative has already been shown to improve heart function and survival rates in hundreds of people suffering from heart disease. A study in the New England Journal of Medicine found that TAVR significantly reduces the risk of death and symptoms of congestive heart failure, in comparison to standard medical therapy (Smith, 2011). Furthermore, total 12-month costs were lower and qualityadjusted life years were higher in patients undergoing TAVR than patients undergoing open-heart valve replacement surgery (IU Health Physicians, 2013).

Figure 7. A. Edwards SAPIEN Transcatheter Aortic Valve with inflated balloon, B. Tri-leaflet Design in Physiologic Closed Position, C. 100-year-old TAVR recipient Maxine Tuttle, D. Edwards Transfemoral Balloon Catheter (Edwards Lifesciences, 2013) 7

The Edwards SAPIEN Transcatheter Aortic Valve is most commonly used for this procedure. This device was created by Edwards Lifesciences and approved by the FDA in November of 2011 U.S. (Food and Drug Administration, 2013). The innovative design consists of a tri-leaflet valve made of bovine pericardial tissue, surrounded by a balloon-expandable stainless steel stent for insertion and structural purposes. A polyethylene terephthalate (PET) skirts encircles the bovine tissue to prevent leakage of blood between the valve and the cardiac tissue. The valve is placed around a balloon at the end of a catheter, inserted through a small incision in the leg, and threaded up through the blood vessels to the aortic valve. The balloon is then inflated, which expands the stent and pushes the damaged valve aside, and then the catheter is removed and blood starts flowing normally (Edwards Lifesciences, 2013). An interesting aspect of this design is its combination of three different categories of materials to enhance its performance: a biological tissue, a polymer, and a metal. The bovine tissue is used for its biocompatibility and similar function to the native tissue. While xenographic tissue is less effective than autographic tissue, it is easier to obtain (larger supply). Furthermore, this particular bovine pericardial tissue is also used for the Carpentier-Edwards PERIMOUNT surgical valve and has been proven to function well. A tissue heat treatment called the Carpentier-Edwards ThermaFix process is used to minimize calcification of the tissue and preserve performance. Leaflets are matched for elasticity and thickness for durability. The PET was used because of its low surface coefficient allowing smooth blood flow, and its surface chemistry that resists protein adsorption. And finally, stainless steel (316L) was used for the stent because of its inertness, high strength and formability, low cost, and availability. Stainless steel offers long-term fatigue, fracture, and corrosion resistance, and does not cause an immune system reaction. More costly shape-memory alloys (E.g. Nitinol) may have improved function and decreased thrombogenicity (Thierry, 2002), but are much more costly. The catheter used for TAVR placement, the RetroFlex Balloon Catheter, is made of a material because of low friction and moderate stiffness that allows the catheter to bend around the circulation while still remaining rigid enough to keep its shape. The frame heights of the valve (14.3mm for the small valve, and 16.1mm for the large valve) were designed to minimize the risk of conduction system interference in the heart. Like any biomedical device, TAVR has its limitations. While transcatheter replacement procedures showed improved survival rates and much shorter hospitalization periods, the transcatheter approach led to increased risk for strokes (5.1% vs. 2.4%, P=0.07) and major vascular complications in the legs (11.0% vs. 3.2%, P